BONE MARROW FAILURE (BMF) SYNDROME : - Diagnosis : marked pancytopenia or reduction in two of three cell

AA, PNH, PRCA, and Agranulocytosis lines; peripheral blood smear shows reduced platelets and

- BMF : inadequate blood cell production leading to low RBC, neutrophils, and normal red cells; microspherocytes and giant

WBC, and/or platelet counts in the peripheral blood. platelets suggestive of peripheral destruction are not present; BM

- BMF can be acquired or constitusional, may affect all three blood biopsy markedly hypocellular (overall celullarity <30%, but there

cell lineages (resulting in pancytopenia) or only a single lineage. may be pockets of cellularity, mainly composed by residual

-In most cases, BMF shows a simple deficiency of the related lymphocytes, so-called hot spots); myeloblast should not be

precursor cells, but BMF can also occur with relatively cellular increased; megakaryocytes are almost always absent; marrow

marrows , presumably due to ineffective hematopoiesis, and could cytogenetics should be normal; CD34+ progenitor cells low (while

be associated with cytogenetic abnormalities (MDS) or a CD34+ is normal/increased in MDS; source of clonal expansion in

genetically altered cell (PNH). MDS).

- Relationship between common BMF syndrome (fig.1) - Pancytopenia has many causes (primary marrow diseases or
secondary marrow failure to systemic diseases), of which AA is not
the most common (table 1)

ACQUIRED APLASTIC ANEMIA (AA)

- Rare (2 case/1.000.000 in West), 2-3x more common in Asia
- Most patients are young, mean presenting age 15-25 years
- Risk factors : drugs (AB chloramphenicol, sulfonamide; NSAID
diclofenac, piroxicam, indomethacin, butazones; Allopurinol;
Antithyroid; Anticonvulsant phenytoin, carbamazepine; Gold;
Penicillamine), viral infection, enviromental toxins, radiation
- Pathogenesis : most cases due to immunologically-mediated
destruction of hematopoietic cells by cytotoxic T-lymphocytes
(CTLs) and their cytokine products, esp.interferon-γ and TNF-α.
- Presentation : anemia (fatigue, weakness, headache; in older pts
dyspnea and chest pain), thrombocytopenia (mainly mucosal
bleeding, usually not brisk unless in the presence of accompanying
physical lesions, as in gastritis and fungal infection of lungs),
infection is unusual at presentation, occasionally not severe AA is
diagnosed incidentally when doing routine blood test or pre- - Marrow failure secondary to systemic diseases causes moderate-
operative evaluation, constitutional symptoms (weight loss, degree pancytopenia, and the underlying illness usually obvious
anorexia, malaise) should be absent. from history and physical examination (e.g., stigmata of alcoholic
- Physical findings : range from a well-appearing pts with minimal liver disease, presence ot other autoimmune disease or infection).
findings to acutely ill pts with signs of systemic toxicity. Cachexia, - After excluding secondary marrow failure, it is important to
lymphadenopathy, splenomegaly should not be seen and suggest distinguish AA from other primary marrow diseases causing
alternative diagnosis. pancytopenia (table 2). Differential diagnosis of AA (fig 3).
- Severe AA (SAA) : two of the following three peripheral blood a candidate for HSCT, family blood donor should be avoided to
count criteria : ANC <500, Platelet <20.000, Reticulocyte count prevent alloimmunisation that may complicate future HSCT and if
(automated) <60.000 or corrected reticulocyte <1%. CMV status is negative or unknown, CMV transmission should be
avoided by either leukoreduction or CMV-negative product use.
Lower platelet goal to prevent bleeding for e.g. 10,000 is usually
well tolerated. AB prophylaxis with oral quinolone and triazol
antifungal may be reasonable if ANC is consistently <200.
Definitive treatment consists of allogeneic HSCT or
immunosuppression; Comparison between HSCT and
immunosuppression (table 3)
- Main factors affecting HSCT successfulness are age and type of
donor.

- Before transplantation, conditioning with cylophosphamide 50

mg/kg/day for 4 days with or without anti-thymocyte globulin
(ATG) is used. Transplantation-related morbidity and mortality is
related to graft-versus-host-disease (GVHD) and infection (not
always easily separable). GVHD and mortality risk increase with
recipient age (>40 years of age). The source of donor cells may be
important: G-CSF mobilized peripheral blood CD34+ cells
produced a higher rate of chronic GVHD and mortality in younger
patients than did BM cells in retrospective studies. Modest
numbers of erythrocytes and platelet transfusions do not appear to
increase the risk of graft rejection, esp with leukocyte-depleted
products
- 70% pts will lack a suitably matched sibling donor. Overall,
results of matched unrelated donor (MUD) transplant have been
about half as good as with HLA-matched family members, but
outcomes are improving with recent modifications of conditioning
regimens and high-resolution molecular typing for donor selection.
- Immunosuppression using regimens combining ATG and
- Treatment : Supportive treatment with PRC or platelet Cyclosporine A (CsA) is standard of Tx. About two-third of pts
transfusions, hematopoeitic growth factor, and antibiotics. If pts is improve to transfusion-independence and overall 5-year survival
rates are comparable to HSCT. Immunosuppression is almost - Other treatment : non-immunosuppression regimen has emerged
always preferred in older pts, esp if the ANC is not severely as an attractive alternative to immunosuppressants as salvage
decreased (fig 3). Protocol : horse ATG 40 mg/kg/day for 4 days or therapy in pts refractory to an initial course of horse ATG. TPO-
rabbit ATG 3,5 mg/kg/day for 5 days with corticosteroid (CS) such receptor agonist eltrombopag showed activity as single agent in
as MP at 1 mg/kg during first 2 weeks to ameliorate serum horse-ATG refractory pts. At a daily dose 150 mg, eltrombopag
sickness. Horse ATG gives better hematologic response and 3- produced hematologic response in 40-50% pts, in most in two or
years survival rate compared with rabbit ATG. three hematopoietic lineages. This well-tolerated outpatient
- Major toxicities of ATG include immediate allergic reaction, regimen was continued until pts showed either no response,
serum sickness, and transient blood count depression. Anaphylaxis relapse, or had a rare robust recovery in counts, in which case the
is rare, but has been fatal and may be predictable by skin testing. drug was quickly tapered to off. Clonal evolution occured in 15-
Treatment of ATG allergy is mainly symptomatic: IV hydration, 20% of cases. In several countries, eltrombopag has been approved
antihistamines (urticaria), meperidine (rigors), and increased doses as single agent in pts who had insufficient response to initial
of CS (symptomatic serum sickness). immunosuppresion. Eltrombopag can be added to horse ATG and
- CsA is begun at 10 mg/kg in adults and 12 mg/kg in children, CsA as first-line therapy with high overall hematologic response
with dose adjustments to maintain blood levels about 200-400 (80-90%) and complete response rate (40-60%), with best results
ng/ml. We administer CsA for 6 months following ATG. It is when all three drugs were administered beginning on day 1.
common for CsA to be tapered after 6-12 months with limited data Androgen hormone danazol can improved blood count in refractory
to support this practice. Renal and liver function monitoring is SAA (not as first line Tx) but caution to monitor liver function test.
required to avoid nephrotoxicity; hypertension, gingival - Prognosis is strongly correlated to hematologic response at 3
hypertrophy, and tremulousness, which are common side effects. months, esp the robustness of blood count recovery (absolute
reticulocyte and platelet count). Pre-therapy absolute reticulocyte
has also been correlated with a better response rate and survival.
Neutrophil count did not correlate with hematologic response
outcomes but associated to short-term mortality.
- Despite lack of progress in developing more efficacious
immunosuppresive regimens, survival in SAA has improved esp
among nonresponders to an initial course of horse ATG, with
survival in 5 years increasing from 23% in 1990s to 57%. This
improvement has been attributed to better supportive care (with
antifungals) and more effective salvage therapies with repeat
immunosuppression and salvage HSCT. Rates of graft rejection
and survival also improved with better transplantation and
supportive care protocols, less immunogenic blood products, and
closer HLA matching between unrelated donors and recipients with
high-resolution tissue typing. However, rates of acute and chronic
GVHD have remained steady over the years.
- Even after hematologic response to ATG, blood counts may fall,
esp on withdrawal of CsA. Reinstitution of CsA usually suffices,
but retreatment with ATG may be necessary and relapse is
sometimes irreversible and fatal. Evolution to a clonal hematologic
disease occurs in about 15% of pts over the decade after initial
therapy, manifesting as a dysplastic BM or cytogenetic
abnormalities.

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

- Refractory or relapse after initial horse ATG : repeated
- Rare, non-malignant clonal expansion of the BM, which can
immunosuppresion with rabbit ATG or alemtuzumab. Both second-
produce a clinical triad of (1) hemolysis, (2) venous thrombosis,
course of rabbit ATG and alemtuzumab give hematologic response
and (3) aplastic anemia.
in 30-40% refractory pts. In relapse, alemtuzumab without
- Pathogenesis : acquired somatic mutation in a gene called PIG-
cyclosporine gives 55% hematologic response.
A, leads to deficient synthesis of a glycolipid moiety called
glycosylphosphoinositol (GPI). GPI serves as a membrane anchor no thrombocytopenia; (6) Marrow failure presenting as frank AA
for ±20 proteins normally expressed on hematopoietic cell surface. with associated PNH should be treated with HSCT or
As a result, PNH progenitor cells deficient in all GPI-anchored immunosuppression.
proteins including CD55 and CD59 protein which are essential in
preventing complement and intravascular hemolysis of RBCs. PIG- MYELODYSPLASIA SYNDROME (MDS)
A mutant cells probably present in normal adult marrow, but clonal - Heterogeneous group of clonal myeloid stem cell neoplasm
expansion of these cells is unusual. Pts with AA and less characterized by ineffective hematopoiesis and variable tendency
commonly with MDS, often has variable size of PIG-A mutant to progress to AML. Median age of dx is mid 60s, rare before 40 y.
cells (PNH clones). Small clone size does not cause clinically - Etiology : clonal malignant expansion of myeloid stem cells due
significant disease. Severe hemolysis and thrombosis typically to acquire somatic mutations and distinguished by AML by <20%
occur only in pts with large clones (>50%). myeloblast in BM. Majority of cases (85%) occur de novo w/o
- Presentation : can be presented at any age. (1) intravascular definitive antecedent cause, 15% secondary to prior ChemoTx
hemolysis : classically as periodic bouts of dark urine (alkylating agent and topoisomerase inhibitor), ionizing radiation,
(hemoglobinuria) in the morning (hemoglobinuria however only AA esp as a late event after immunosupressive Tx, PNH, and T
reported in 25% pts during initial examination); (2) venous cell-LGL (large granular lymphocytosis). Latency period between
thrombosis in unusual sites especially hepatic, mesenteric, portal exposure and the development of secondary MDS typically 2-10 y.
veins, and intracranial veins. Thromboses can cause abdominal BM is typically hypercellular, implying that ineffective
pain or stroke ; (3) marrow failure : subtle or overt sign of bone hematopoiesis rather than the absence of stem cell causes the
marrow failure (accompanying leukopenia and thrombocytopenia cytopenia. Early MDS (refractory anemia) is characterized by
results in pancytopenia) despite a relatively cellular BM is clonal expansion of dysplastic stem cell with defective
common. Long-term repeated episodes of hemoglobinuria may differentiation and increased apoptosis of myeloid/erythroid
causes iron-deficiency. precursors. Late MDS (transition to leukemia) is associated with
- Diagnosis : PNH is suspected in pts with following findings : (1) reduced apoptosis. Specific genetic abnormality in particular
signs intravascular hemolysis (elevated LDH, symptoms of abnormalities of chromosome 7 and complex karyotype, predispose
macroscopic hemoglobinuria is not always present) of undefined to leukemic transformation. Death due to MDS usu occurs from
cause (i.e.Coombs-negative), (2) accompanying neutropenia and or complication of cytopenias, before the disease progress to AML.
thrombocytopenia is common, (3) venous thrombosis in unusual Many pts succumb first to comorbidity of the elderly.
sites. PNH clones should be sought in pts with AA and MDS with - Clinical features : anemia is the most common cytopenia at
peripheral blood flow cytometry. Special test : Ham’s test and presentation. However 80% pts have varying degrees of other
Sucrose-water test; both detect abnormal sensitivity of PNH RBCs cytopenias (thrombocytopenia or neutropenia). About 17% of
to complement. These tests are sensitive and specific for PNH but unexplained anemia in the elderly have peripheral blood count
very subjective (operator-dependent). Gold standard flow- consistent with MDS. Bleeding out of proportion to the severity of
cytometry. thrombocytopenia is common due to platelet dysfx. Similarly,
- Differential diagnosis : autoimmune hemolytic anemia esp. neutrophil dysfx can lead to bacterial and fungal infections w/o
Paroxysmal cold hemoglobinuria and cold agglutinin syndrome. severe neutropenia. Leukocytosis and splenomegaly are rare. The
- Treatment : (1) transfusion to maintain Hgb levels. Use of clinical course is variable : pts may be asymptomatic or have mild
washed erythrocytes is not necessary and risk of secondary anemia progressing to transfusion dependence over many years,
hemochromatosis from repeated transfusion is somewhat lower while others have an agressive course of progressive pancytopenia
because continual loss of iron from hemoglobinuria; (2) iron and rapid evolution to acute leukemia.
supplementation may be required; (3) CS usually in moderate - Diagnosis : minimum Dx criteria of MDS require :
doses (30-50 mg prednisone on alternate days) to control 1.Unexplained persistent cytopenia (one or more cell lines) and
hemolysis; (4) Monoclonal antibody directed to active component 2.Evidence of either clonality (MDS-defining cytogenetic
of C5, Eculizumab blocked intravascular hemolysis, which abnormality) or unambiguous dysplastic marrow morphology
translated to a clinically significant improvement in anemia, (dysplasia in at least 10% of the cells of one of the myeloid
transfusion requirement, and quality of life. Eculizumab at a fixed lineages or excess blast)
dose 900 mg every 2 weeks (not body weight-based dosing) also Blood smear : usu shows macrocytosis (in minority normocytic),
dramatically reduce the risk of clinical thromboses, which is the hypogranular neutrophils, circulating micro-megakaryocytes.
major cause of morbidity and mortality in pts with PNH; (5) BM biopsy : 80% hypercellular, 20% hypocellular or fibrotic (poor
prophylaxis for thrombosis with warfarin is controversial. Warfarin prognosis). Increase in myeloblast and dysplatic white cell or
prophylaxis may be indicated in pts with large clone (>50%) and megakaryocyte morphology can be seen. Abnormal localization of
immature precursors (ALIPs) near bony trabeculae is characteristic should be monitored by measurement of the anti-factor Xa activity.
of MDS. Mononuclear, small, or dysplastic CrCl should be estimated before initiation of LMWH in elderly as
they may have renal dysfunction despite having normal creatinine
THALASEMIA values. Fondaparinux is contraindicated in severe renal impairment
AGRANULOCYTOSIS (table 4). The safest choice of anticoagulation in pts w/severe renal
- Most agranulocytosis is drug-associated. Idiopathic pure white impairment is UFH.
cell aplasia (without exposure to a suspicious drug) is exceedingly -Monitoring anti-Xa le levels should also be used in severely obese
rare. pts (BMI ≥40) who receive therapeutic doses of LMWH and
- Drugs associated with agranulocytosis : should be considered for those who are obese (BMI ≥30), esp if the
Heavy metals gold; NSAIDs; Anticonvulsant phenytoin, pts has moderate to severe renal insufficiency (CrCl <60 ml/min).
carbamazepine; Antithyroid drugs; Sulfa drugs e.g sulfasalazine, LMWH has close to 100% bioavailability but is primarily
dapsone, sulfa antibiotics; Antibiotics; Antipsychotics/sedatives/ distributed in the plasma and highly vascular tissues with little
antidepressants e.g. phenothiazine, tricyclics, barbiturate, SNRI; distribution in fat tissue. As obese pts have a lower proportion of
Miscellanous allopurinol lean body mass compared with their total body weight, concern for
- Diagnosis and treatment: pts is usually older with a history of potential overdosing of LMWH in obese pts has led some
clear exposure to an incriminated agent, usually with the clinicians capping the dose at a maximum absolute dose, typically
introduction of the drug in the preceding 6 months. Absent at the maximum prefilled syringe dose.
neutrophils on smear should lead to a confirmatory BMA. Classic - Target therapeutic range of anti-Xa for enoxaparin is 0.6 to 1.2
presentation is fever and sore throat. Recovery occurs U/ml for twice-daily dosing and 1 to 2 U/ml for once-daily dosing.
spontaneously but over a highly variable period, from a few days to HEMATOLOGIC DISEASE IN PREGNANCY
several weeks. In practice, G-CSF is almost always administered INTERPRETATION OF HEMATOLOGIC TESTS
wihout clear evidence of efficacy. Fever and signs of infection
require prompt administration of broad-spectrum parenteral
antibiotics. Mortality remains substantial (about 10%) due to the
combination of patient age, comorbid condition, and lethal sepsis.

DISORDERS OF HEMOSTASIS I (thrombocytopenia)

DISORDERS OF HEMOSTASIS II (hemophilia, vWD)
VENOUS THROMBOEMBOLISM
CONSULTATIONS IN ANTICOAGULATION
Prophylaxis and treatment of VTE in pts with cancer in specific
clinical setting
- Malignancy ↑ risk for VTE due to : (1) ↑ production and release
of microparticles containing procoagulant such as tissue factor
result in hypercoagulability; (2) vessel wall damage; (3) blood flow
stasis from extrinsic compression, (4) prolonged immobility, (5)
anticancer therapy including cytotoxic chemotherapy, certain
antiangiogenic agents, or hormonal therapy; (6) increasing use of
long-term indwelling catheters, e.g.,CVC
- Tumor angiogenesis, progression, growth, and metastasis are
enhanced by, and depend on activation of blood coagulation.
- Cancer most commonly a/w VTE : pancreas, stomach, kidney,
lung, ovary, bladder, certain hematologic malignancies, testis, and
gliomas of the brain.
- Selecting anticoagulant agents for VTE : UFH, LMWH,
fondaparinux, and oral anticoagulants are the mainstay of therapy.
LMWH is preferred for both prevention and treatment of VTE in
cancer pts as studies show superior efficacy without ↑ risk of
bleeding compared to oral anticoagulant. LMWH undergoes renal
excretion, hence pts with kidney impairment who receive LMWH